Microcephaly and mental retardation have been noted in persons exposed in utero within 2000 meters of the hypocenter. Mental retardation correlated strongly with exposure at less than 15 weeks' gestation. The development of microcephaly appears to be independent of gestational age. The central nervous system malformations noted in the single autopsy of an in utero exposed survivor are similar to those found experimentally. The retardation of height and weight in individuals exposed prenatally, in infancy, or in early childhood is less well documented and is influenced by environmental factors other than radiation.
The numbers of eosinophils and mast cells observed at the tumor border of 331 rectal cancers from patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP), protocol R-01, were correlated according to overall survival rate, as well as Dukes' stage, tumor differentiation, nodal status, degree of lymphoid and stromal reactions, sex, and age. Life table plots disclosed a significantly better overall survival rate when ten or more eosinophils per 30 oil immersion fields were found. However, the numbers of eosinophils were strongly associated with Dukes' stage and, when life table plots were adjusted for Dukes' stage, this relationship to survival rate was not evident. On the other hand, overall survival rate was significantly higher in patients in whom 0 to three mast cells per 30 oil immersion fields were found than in those patients in whom four or more mast cells were found. This relationship persisted even when life table plots were adjusted for treatment, Dukes' stage, or nodal status, and indicated that the number of mast cells further defined survival rate among patients exhibiting Dukes' A, B, and C stages. It is concluded that numbers of eosinophils and mast cells may play a role in the natural history of rectal cancer but only the latter represents a prognostic parameter independent of Dukes' stage or nodal status. The mechanism whereby mast cells may exert this effect is at present unknown.
Hyperplastic changes of intrahepatic peribiliary glands have rarely been reported, with the exception of hepatolithiasis. To determine whether there are any hyperplastic changes in the glands in livers without hepatolithiasis, we examined 1,000 consecutive autopsy liver specimens that had no hepatolithiasis. The glands were divided into intramural mucous glands and extramural seromucous glands. The hyperplastic changes were found in "normal" livers and in livers with various hepatobiliary diseases, and they were classified into three categories: hyperplasia of intramural glands (49 cases; 4.9%), hyperplasia of extramural serous acini (35 cases; 3.5%), and hyperplasia of extramural mucous acini (92 cases; 9.2%). Two or more of these three hyperplastic changes occasionally coexisted in the same liver. Hyperplasia of intramural glands was seen rather evenly in normal livers and in livers with various hepatobiliary diseases. Prevalence of hyperplasia of extramural serous acini was high in intrahepatic cholangitis and submassive hepatic necrosis. Prevalence of hyperplasia of extramural mucous acini was high in cirrhosis, submassive hepatic necrosis, cholangitis, systemic infection, and extrahepatic biliary obstruction. The hyperplastic intramural glands and mucous acini of extramural glands contained more neutral, carboxylated, and sulfated mucin than normal glands. Although their pathogenesis is unclear, these hyperplastic changes may enhance seromucous secretion into biliary lumens and may lead to biliary dysfunctions such as retardation of bile flow and increased bile viscosity. These hyperplastic changes may be preexisting conditions predisposing to hepatolithiasis.
The protocols of 1,000 consecutive adult patients autopsied during the period June 1983 to December 1988 were retrospectively analyzed and the findings were compared with clinical diagnoses. The autopsy rates during this period ranged between 23% and 27% of hospital deaths. Eighty-seven percent of the autopsied patients were between 15 and 59 years of age. Major discrepancies between the autopsy reports and the clinical diagnoses were present in 31.7% of all autopsy reports reviewed. Infectious diseases were the most common cause of death (46.8%), followed by cardiovascular diseases (17.1%) and neoplastic diseases (14.3%). Infections were clinically recognized in 66.7% of cases and were missed or found to be incorrect in 33.3% of cases. Tuberculosis comprised 33.8% of the major bacterial infections and was clinically diagnosed in 82% of cases. Eighty-nine percent of the major fungal infections were not suspected clinically. Rheumatic heart disease (43.8%) was the most common cardiovascular disorder and was clinically diagnosed in 93.3% of cases. Pulmonary vascular episodes were the least common cause of death and were not suspected clinically in 62.9% of cases. Malignancies were incorrectly diagnosed in 25.8% of cases. We conclude from this study that routine autopsies revealed major unexpected findings that are of clinical importance, and that a continued emphasis on autopsy evaluation is necessary for the improvement of the quality of patient care.
Low-affinity nerve growth factor receptor (p75) is a member of the tumor necrosis factor receptor family. It may modulate the binding of nerve growth factor (NGF) to the functional high-affinity receptor tyrosine kinase (trk) A. NGF is thought to be responsible for growth, apoptosis, and function of the nervous system. The presence of this receptor (p75) was determined in a large group of neural and nonneural tumors and fetal and adult tissues. One thousand one hundred fifty tumors were analyzed with monoclonal antibody for p75, along with selected normal fetal and adult tissues. Immunoreactivity for p75 was present in adult pericytes, perivascular fibroblasts, basal cells of several types of epithelia, perineurial cells, and dendritic reticulum cells. Additionally, a wide zone of subepithelial mesenchyme and skeletal muscle were positive in the first-trimester fetus, but were diminished or negative in the adult. Consistently positive nonneural mesenchymal tumors included dermatofibrosarcoma protuberans (DFSP), embryonal and alveolar rhabdomyosarcoma, synovial sarcoma, and spindle cell hemangio(endotheli)oma. Schwann cell tumors, ganglioneuroma, granular cell tumor, and malignant peripheral nerve sheath tumor (MPNST) were also p75 positive. Mesenchymal nonneural tumors that were variably positive (32% to 69%) for p75 included fibrosarcoma variants, solitary fibrous tumor, hemangiopericytoma, spindle cell lipoma, Ewing's sarcoma, mesenchymal chondrosarcoma, and malignant melanoma. Nervous system tumors such as paragangliomas, neuroblastoma, meningioma, and perineurioma and nonneural mesenchymal tumors, including extraskeletal osteosarcoma, benign fibrous histiocytomas, fibromas, alveolar soft part sarcoma, epithelioid sarcoma, smooth muscle and gastrointestinal stromal tumors, and angiosarcomas, were almost always negative for p75. Epithelial tumors that were consistently positive included mixed tumor and adenoid cystic carcinoma, whereas mesothelioma, adenocarcinomas, and most squamous cell carcinomas were negative. p75 is not a specific marker for nerve sheath tumors. It is present in a variety of other mesenchymal tumors including synovial sarcoma and in CD34-positive tumors such as DFSP, spindle cell lipoma, and hemangiopericytoma. The presence of p75 in nonneural tumors such as DFSP and rhabdomyosarcoma mimic its presence in early fetal mesenchyme and skeletal muscle, suggesting oncofetal expression in these tumors. p75 may be useful to distinguish DFSP from benign fibrous histiocytoma.
In 1,405 patients who died at the General Hospital of Trieste in 1974 and 1978, malignant neoplasm was revealed at autopsy. Clinical diagnosis was accurate in 54 per cent of these patients. The tumor was clinically suspected in 19 per cent and was undiagnosed in 27 per cent. The accuracy of the clinical diagnoses varied significantly according to the primary site and type of tumor; accuracy was inversely related to the age of the patient and varied also according to the department of the hospital to which the patient had been admitted. This latter variation is age-dependent, too. In the past decades clinical diagnosis of malignancy has not greatly improved, although the autopsy rate has almost everywhere strongly decreased, representing a heavy handicap in the epidemiologic research on cancer as a cause of death.
The prognosis of prostate cancer is mainly determined by the presence or absence of metastases. Nevertheless, the metastatic pathways in prostate cancer are not entirely understood. Among 19,316 routine autopsies performed from 1967 to 1995 on men older than 40 years of age, the reports from those 1,589 (8.2%) with prostate cancer were analyzed. Hematogeneous metastases were present in 35% of 1,589 patients with prostate cancer, with most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and adrenals (13%). Several lines of evidence suggested the existence of a backward metastatic pathway through veins from the prostate to the spine in addition to classical hematogeneous tumor spread via the vena cava. First, there was an inverse relationship between spine and lung metastases, suggesting that metastasis to the spine is independent of lung metastasis. Second, the maximum frequency of spine involvement occurred in smaller tumors (4 to 6 cm) as compared with the maximum spread to lung (6 to 8 cm) and liver (>8 cm), suggesting that spine metastases precede lung and liver metastases in many prostate cancers. Third, there was a gradual decrease in spine involvement from the lumbar to the cervical level (97% v 38%), which is consistent with a subsequent upward metastatic spread along spinal veins after initial lumbar metastasis. The results of this study show that bone, lung, and liver are the most frequent sites of distant prostate cancer metastases. Besides the cava-type of metastasis through lung passage, there are strong arguments for the existence and clinical significance of a backward venous spread to the spine, which is likely to occur early in the metastatic process.
We previously reported that α(1,6)fucosyltransferase (Enzyme class 220.127.116.11) activity and expression are increased in colorectal cancer, suggesting a role for this enzyme in tumor development and progression. However, the possible impact of α(1,6)fucosyltransferase activity or expression on clinical outcomes in colorectal cancer patients has never been studied. Thus, the present study was conducted to determine the value of α(1,6)fucosyltransferase as a prognostic factor for colorectal cancer. α(1,6)Fucosyltransferase expression was analyzed using immunohistochemistry in 141 colorectal tumors, and α(1,6)fucosyltransferase activity was determined in 39 tumors. A complete standardized follow-up of patients was documented until the end of the observation period of 5 years or patient death. Univariate analysis demonstrated the absence of a correlation between enzyme activity and disease evolution. However, in patients with moderate or strong α(1,6)fucosyltransferase expression, a significant decrease in the overall (P = .04) and disease-free (P = .03) survival rates was observed. In addition, when local and distant disease recurrence were considered separately, enzyme expression was found to correlate with local tumor recurrences (P = .01). Furthermore, multivariate analysis showed that α(1,6)fucosyltransferase expression has independent value for predicting tumor recurrences and, specifically, local recurrences. These findings suggest that α(1,6)fucosyltransferase expression may be a good indicator of poor prognosis in colorectal cancer and, therefore, a helpful tool to choose the most effective treatment.
L1 cell adhesion molecule (CD171) represents a strongly unfavorable prognostic biomarker for ovarian and endometrial carcinomas. Here we carried out an immunohistochemical survey of L1 expression in normal adults and in a broad range of benign and malignant tumors using monoclonal antibody L1-11A and the novel monoclonal antibody L1-14.10. In normal tissues, L1 was expressed in the collecting tubules of adult tissues and pediatric kidney and in peripheral nerve bundles. In tumors of the female genital tract, L1 was detected in adenocarcinomas of the cervix and fallopian tubes, in addition to ovarian and endometrial carcinomas. Nongynecological tumors expressing L1 comprised malignant melanoma, colon adenocarcinoma positive to chromogranin, clear-cell adenocarcinoma of the urinary bladder, pheochromocytoma, small cell lung carcinoma, and tumors of the nervous system. L1 was absent in breast carcinoma, gastrointestinal tract carcinomas, gastrointestinal carcinoids, renal clear-cell carcinomas, prostate adenocarcinomas, and mesotheliomas. Surprisingly, L1 expression in established breast and renal carcinoma cell lines was not a predictor for its presence in these human tumors in vivo. Our results suggest that L1 expression in tumors is not ubiquitous but restricted to certain subtypes and may be a helpful molecular marker for differential diagnosis and target for antibody-based therapy.
The primary causes of death in 1000 autopsy cases of perinatal death during the eight years from 1972 through 1979 are discussed. On the basis of the clinical data and gross and microscopic findings, each case was assigned to one of the following categories of primary causes of death: pulmonary hyaline membrane disease, infection, malformation, anoxia, immaturity, maternal causes, other causes, and unaccounted for. Definitions of perinatal infant diseases, essential points of diagnosis, and statistics relating to perinatal infant death are also discussed.
On review of 115 poorly or undifferentiated lung cancers from 671 lung tumors resected over a 7-year period, we have found 38 cases of basaloid carcinoma. The cardinal histopathologic features distinguishing this tumor from other non-small cell lung cancers are a lobular growth pattern of small cells with moderately hyperchromatic nuclei, with no prominent nucleoli, and with scant cytoplasm, a high mitotic rate, and peripheral palisading. Basaloid carcinoma was present in a pure form in 19 cases and the other 19 tumors were of a mixed, but prominent, basaloid type associated with squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. The immunophenotype of basaloid cancers was close to that of basal bronchial epithelial cells, with a low level of expression of low molecular weight cytokeratins. Staining for neuroendocrine markers was infrequent and inconsistent. Ultrastructural study showed an absence of neurosecretory granules and the presence of some squamous and/or glandular differentiation. This morphologic and immunologic phenotype suggests that basaloid carcinoma is derived from a pluripotent reserve cell or a basal bronchial epithelial stem cell. This unique histologic form of lung tumor has a poor prognosis, with a median survival rate of 22 months for stage I and II disease. This justifies classification of basaloid carcinoma as a distinct form of lung cancer, separate from small cell lung carcinoma.
Glomerulonephritis (GN) characterized by immune complex deposits typical of postinfectious GN but with a paucity or absence of overt clinical symptoms and/or urinary abnormalities may occur after a group A streptococcus infection. The overall incidence of this type of subclinical GN is not known. To address this question, electron microscopy findings in 1012 consecutive renal biopsy specimens (952 native kidney, 60 transplant) examined by a single renal pathologist from August 1999 to April 2002 were retrospectively reviewed for the presence of distinct subepithelial and intramembranous deposits indicative of postinfectious GN. Such deposits were noted in 83 biopsy specimens, including 26 with a primary diagnosis of postinfectious GN (acute, persistent, or latent) and 57 in which these deposits were an incidental finding. In each of the latter 57 cases, some or all of the deposits showed partial or extensive loss of electron density typical of partially or largely resorbed deposits. A diagnosis of incidental postinfectious GN was not made in any biopsy specimen exhibiting another immune complex-related glomerular disease that could possibly account for the deposits, composing 443 of the 1012 biopsy specimens examined. Thirty of the 57 biopsy specimens with incidental postinfectious GN showed mesangial hypercellularity, although this was focal and segmental in all but 3 cases and was not accompanied by the endocapillary hypercellularity typical of acute postinfectious lesions. Immunofluorescence microscopy revealed glomerular deposits of C3 in >90% of these biopsy specimens and IgM deposits in 66%, but only rare IgG, IgA, and Cq deposits. Twenty-three (40%) of these 57 biopsy specimens exhibited diabetic nephropathy, either alone or in combination with another lesion; for perspective, only 128 (13%) of the 1012 biopsy specimens examined showed evidence of diabetic nephropathy. In summary, incidental evidence of resolving or largely healed postinfectious GN was noted in up to 10.5% of renal biopsy specimens (57 of 543, not including specimens with a primary diagnosis of an immune complex-related glomerular disease). The recognition of such lesions is potentially important in the interpretation of certain renal biopsy specimens.
We present the preoperative findings of 102 patients who underwent successful splenectomy for advanced schistosomiasis japonica. All patients were symptomatic for schistosomiasis and had splenomegaly greater than or equal to II according to the Hackett criteria. Before surgery, all patients underwent clinical examination including full blood count; fibrinogen and serum protein levels; liver function tests; and serology for hepatitis B, C, and D. Ultrasound examination of the liver and spleen and liver histology for evidence of pathology were also undertaken. Ninety patients had a treatment history for schistosomiasis. Fifty-six patients were seropositive for hepatitis B virus antibody, and 6 patients were seropositive for hepatitis C virus antibody. Immunohistochemical testing of the liver samples confirmed that 45 patients were positive for hepatitis B virus surface antigen, thereby indicating active infection. A total of 66.7% of patients had fibrosis stages II to III by ultrasound; and 76.5% of patients had portal vein inner diameter greater than 12 mm, indicating portal vein hypertension. A total of 83.2% of patients showed various stages of esophageal varicosis via x-ray, and 81.4% had fibrotic stages III to IV by liver biopsy. Coinfection with hepatitis B virus accelerated the development of liver fibrosis. There was moderate concordance between the fibrosis assessed by ultrasonography and histopathology, indicating that ultrasound underestimates the true pathology. Combined assessment is needed to improve the diagnosis of clinical hepatic fibrosis.
In our survey of 102 cases of intrahepatic cholangiocarcinoma, 71 peripheral type cases and 31 hilar type cases were observed, the former being prone to metastasize to remote organs and lymph nodes when compared with the latter. These cases were histologically classified into nine histologic types according to the predominant features and rearranged into three groups (well-differentiated, less-differentiated, and uncommon). Although most of these cases were mucin-producing adenocarcinomas with variable grades of differentiation (92 of 102; 90%), several uncommon types were also encountered (ten of 102; 10%), such as adenosquamous, squamous, mucinous, or anaplastic carcinoma. Remote organ metastases were observed more frequently in the less-differentiated group than in the well-differentiated group. In regard to intrahepatic tumor spreading, expansion via sinusoidal spaces (93%), vascular (52%) or lymphatic (18%) involvement, perineural invasion (16%), replacing growth in the bile duct (12%), and permeation in the portal connective tissue (19%) were observed. The cholangiocarcinomas with the vascular involvement presented a higher tendency of intrahepatic as well as extrahepatic metastasis. For correct diagnosis and treatment of cholangiocarcinoma, it seems to be important to possess some knowledge of these histologic types, including their variations and patterns of intrahepatic spread.
Accurate assessment of human epidermal growth factor receptor 2 is critical for the management of patients with breast cancer. We set out to study the impact of the 2007 American Society of Clinical Oncology/College of American Pathologists guidelines on the interpretation of human epidermal growth factor receptor 2 IHC results and its correlation with fluorescence in situ hybridization results. Invasive breast carcinomas with IHC HercepTest 3+ were retrieved from the archive of Mayo Clinic Rochester. The human epidermal growth factor receptor 2 slides were rereviewed, and results were recorded as percentage of invasive tumor cells with 3+, 2+, 1+, and 0 staining intensity. Human epidermal growth factor receptor 2 gene amplification by fluorescence in situ hybridization was performed on all tumors with 3+ staining in 70% or less of tumor cells. Of the 141 cases studied, 12 cases showed intense membrane staining in 11% to 30% of the invasive tumor cells and would have been scored as 2+ according to the new American Society of Clinical Oncology/College of American Pathologists guidelines. Of these 12 cases, 6 were positive for human epidermal growth factor receptor 2 gene amplification by fluorescence in situ hybridization (ratio >2.2), 4 cases were negative (HER2/CEP17 ratio of < 1.8), and 2 cases were equivocal (ratio of 1.8-2.2). One human epidermal growth factor receptor 2-positive case showed dramatic intratumoral heterogeneity with high-level amplification (ratio of 12.2) in the IHC 3+ area and no amplification (ratio of 1.0) in the IHC 1+/2+ areas. The 2007 American Society of Clinical Oncology/College of American Pathologists guidelines down-scored 2.8% of tumors from human epidermal growth factor receptor 2-positive (IHC 3+) to human epidermal growth factor receptor 2-negative (IHC 2+ equivocal and fluorescence in situ hybridization negative) in this study. Clinical studies are needed to determine whether the updated guidelines are better at predicting response to anti-human epidermal growth factor receptor 2 therapy.
The distinction between malignant epithelioid pleural mesothelioma (MEPM) and peripheral adenocarcinoma of the lung with pleural invasion (PAL) continues to represent a diagnostic challenge in selected cases. In order to provide comparative data on histologic, histochemical, and immunohistochemical features of these neoplasms, we analyzed 51 ultrastructurally categorized MEPMs and 52 PALs with the periodic acid-Schiff-diastase (PAS-D), mucicarmine, and colloidal iron stains, and a panel of immunohistologic reagents. Antibodies to cytokeratin, vimentin, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Leu M1, the B72.3 antigen, blood group isoantigens (BGI), placental alkaline phosphatase, amylase, S100 protein, and Clara cell antigen were used, as applied to paraffin sections with the avidin-biotin-peroxidase complex technique. Ultrastructural studies revealed long, branching microvilli in MEPM cells in all cases, with length-to-diameter ratios (LDR) of 10:1 or more. In contrast, PAL manifested short, nonbranching microvilli with LDR of 8:1 or less. Reactivity with PAS-D and mucicarmine stains was strictly confined to PAL, and hyaluronidase-sensitive colloidal iron-positivity was restricted to MEPM. However, only 63% and 41% of these respective neoplasms demonstrated such histochemical reactivity. Immunohistologic results correlated well with electron microscopic classification. All MEPMs and PALs were reactive for cytokeratin; in addition, the majority of tumors in each group expressed EMA, and a minority were reactive for vimentin. In adenocarcinomas of the lung, Leu M1 was observed in all cases, CEA was apparent in 96%, B72.3 labeled 84%, and BGI were present in 67%; all PALs expressed at least two of these determinants, but none was seen in any mesothelioma. The other markers included in this study also were observed in some PAL cases, but not in MEPM. These findings suggest that immunohistology parallels electron microscopy in efficacy in the diagnostic separation of MEPM and PAL. Using antibodies to Leu M1, CEA, and the B72.3 antigen, reactivity for at least two of these three markers appears to exclude a diagnosis of pleural mesothelioma. The other glycoproteinaceous, oncoplacentofetal, and cytoplasmic antigens we studied can be used to reinforce such a determination, since their distribution is confined to adenocarcinomas.
One hundred four cases of sebaceous carcinoma that arose from ocular adnexa, with at least five years' follow-up information following diagnosis, were studied to extend the authors' previous observations on various prognostic factors in these tumors. Twenty-three patients died from metastatic disease. Although sebaceous carcinomas elsewhere in the skin are rare, this study establishes that these neoplasms occur much more frequently in the ocular adnexa and have significant morphologic features that identify the more highly lethal carcinomas. The various clinicopathologic features that indicated a bad prognosis were vascular, lymphatic, and orbital invasion; involvement of both upper and lower eyelids; poor differentiation; multicentric origin; duration of symptoms greater than six months; tumor diameter exceeding 10 mm; a highly infiltrative pattern; and pagetoid invasion of the overlying epithelia of the eyelids. In many cases pagetoid change appeared to originate in the underlying sebaceous glands and from there extended to invade the overlying epithelia.
The outcomes of patients with stage I non-small-cell lung cancer (NSCLC) vary greatly, with a 5-year survival rate of approximately 60%. This study evaluated a number of molecular markers that may aid in predicting prognosis in stage I NSCLC after surgical resection. Immunohistochemical (IHC) staining of p53, HER-2/neu, bcl-2 proteins was performed on paraffin-embedded sections from 85 stage I NSCLC patients who underwent surgery and were followed up for 32 to 44 (median, 39.0; mean, 37.1) months postoperatively. Differences in survival rates were evaluated by log rank test. The prevalence of p53, HER-2/neu, and bcl-2 expression in stage I NSCLC is 59%, 29%, and 46%, respectively. HER-2/neu expression is seen more frequently in adenocarcinomas, and bcl-2 is seen more frequently in squamous carcinomas. p53 and HER-2/neu expression in stage I NSCLC is associated with significantly short survival. Patients whose tumors were both p53 and HER-2/neu positive had the worst outcome, with a survival rate of only 20%, compared with 80% in those whose tumors were both p53 and HER-2/neu negative (P = .0003). The survival rates were 54% in patients who were p53 positive but HER-2/neu negative and 50% in those who were in p53 negative, HER-2/neu positive. The differences among these 4 groups were statistically significant (P =.001). Bcl-2 does not seem to be a prognostic factor for survival. Multivariate analysis showed that overexpression of p53 and HER-2/neu, presence of angiolymphatic invasion, and tumor size > 3.0 cm were independent factors predicting poor survival. p53 and HER-2/neu by IHC staining appear to be valuable prognostic markers in stage I NSCLC patients after surgery. The worst outcome was seen in patients who expressed both p53 and HER-2/neu, suggesting that these patients might benefit from additional adjuvant therapy.
Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.
A series of 106 cases of hemangiopericytoma was analyzed. The neoplasms occurred principally in adults (median age, 45 years), were deep seated, and were most common in the thigh (27 cases) and the pelvic retroperitoneum (26 cases). A painless mass was the first symptom in 96 of the patients. The median size of the excised tumors was 6.5 cm. Surgical removal of the tumor was often complicated by hemorrhage because of marked dilatation of the vascular bed in the vicinity of the neoplasm, probably as the result of rapid exchange of blood from the arterial to the venous circulation within the tumor. Microscopically, benign and malignant forms could be distinguished. The latter were characterized by increased cellularity, prominent mitotic activity, and foci of necrosis or hemorrhage. Follow-up information was obtained in 93 cases. Seventy-one of the 93 patients were living (two with recurrence and four with metastasis), and 22 had died (13 as the result of recurrence or metastasis in more than two-thirds of the related causes). Recurrence preceded metastasis in more than two-thirds of the patients with evidence of metastasis. The 10 year survival rate was 70 per cent. The morphologic differences from other mesenchymal tumors showing a hemangiopericytoma-like vascular pattern are discussed, and the close resemblance of hemangiopericytoma to richly vascular forms of fibrous histiocytomas and synovial sarcoma is emphasized. Congenital or infantile hemangiopericytoma is described as a separate entity having a distinctive microscopic pattern and behavior.
Pancreatic cancer is one of the most aggressive and lethal human malignancies in the Western world. A wide variety of intratumor glandular differentiation, including solitary infiltrating cancer cells, is a prominent microscopic finding in pancreatic cancer. We reviewed 114 resected cases of pancreatic ductal adenocarcinoma to investigate the prognostic impact of the degree of solitary cell infiltration, defined by the number of solitary infiltrating cancer cells. The clinicopathologic correlation of solitary cell infiltration was further evaluated. Seventy-six (67%) cases showed 7 or more solitary infiltrating cancer cells in 10 high-power fields and were labeled as having a high degree of solitary cell infiltration. A high degree of solitary cell infiltration correlated significantly with poor overall survival, the grade, lymphatic invasion, and lymph node metastasis. Multivariate analysis revealed that the degree of solitary cell infiltration, the grade, and the margin status were independent prognostic factors. Grade 1 and 2 tumors with a high degree of solitary cell infiltration, compared with low infiltration, correlated significantly with poor overall survival. Grade 3 tumors showed a worse overall survival than grade 1 and 2 tumors with either a high or a low degree of solitary cell infiltration. Immunohistochemical analysis showed that a high degree of solitary cell infiltration correlated with reduced E-cadherin and increased vimentin expression. In conclusion, solitary cell infiltration is a significant prognostic indicator and serves as a morphological clue to epithelial-mesenchymal transition in pancreatic cancer.
We performed a prospective multiparametric correlative clinical, histopathologic, and immunologic analysis of 117 ocular adnexal lymphoid proliferations developing in 108 patients between October 1977 and July 1987. The ocular adnexal lymphoid proliferations were distributed among the 108 patients as follows: orbit 69 (64%), conjunctiva 30 (28%), and eyelids nine (8%). The 117 ocular adnexal lymphoid proliferations were classified as follows: polyclonal lymphoid hyperplasia, 32 (22 orbit, nine conjunctiva, one eyelid) (27%); monoclonal B cell lymphoma, 81 (48 orbit, 25 conjunctiva, eight eyelid) (69%); null cell lymphoma, one (orbit) (1%); and histologically indeterminate, three (one each: orbit, conjunctiva, eyelid) (3%). Patients presenting with ocular adnexal polyclonal lymphoid hyperplasia and monoclonal B cell lymphoma, and patients developing unilateral and bilateral ocular adnexal lymphoid proliferations did not differ significantly with respect to age, sex, presenting complaints, duration of symptoms, or ophthalmic findings. Classifying ocular adnexal lymphoid proliferations into benign and malignant categories by histopathologic criteria and into polyclonal and monoclonal B cell categories by immunophenotypic criteria was not useful in predicting eventual outcome, including the occurrence of extraocular lymphoma. However, the clinicopathologic characteristics did differ according to the anatomic site of involvement and histopathology of the ocular adnexal lymphoid proliferations. Lymphoid infiltrates of the conjunctiva were associated with a lower incidence of extra-ocular lymphoma (20%) than were those of the orbit and eyelid, 35% and 67%, respectively (statistically significant, P less than .03). Ocular adnexal small lymphocytic and intermediate lymphocytic lymphomas were less often associated with extra-ocular lymphoma than were ocular adnexal lymphomas of all other histologic types, 27% and 46%, respectively (P less than .09). However, the single most important and statistically significant prognostic factor in these patients was the extent of disease at the time of presentation with an ocular adnexal lymphoid proliferation (P less than .001). Eighty-six percent of patients presenting with a unilateral or bilateral clinical stage lE ocular adnexal lymphoid proliferation, regardless of the histopathology or the immunophenotype, had a benign indolent clinical course and failed to develop ocular or extra-ocular lymphoma during a median follow-up period of 51 months. The results of this study substantially improve our understanding of extranodal small lymphocytic proliferations in general, and those of the ocular adnexa in particular.
A group of 13 pathologists belonging to the French Calcitonin Tumor Study Group (GETC: Groupe d'Etude des Tumeurs à Calcitonine) examined the histological slides and medical records of 109 proband cases of medullary thyroid carcinoma (MTC) diagnosed on clinical features. The cases belonged to the various forms of the disease (80 sporadic and 29 familial MTC). The aim of the study was to detect histological predictors for survival by comparing morphological data from patients killed by the disease versus the others. Twenty-seven histological parameters were considered, including cellular heterogeneity, shape of the cells, and cytoplasmic characteristics. Other parameters such as sex, age, and phenotype of the disease were also studied. First, predictive parameters of interest on survival function were selected by univariate analysis (Mantel-Cox test). Then, the extracted parameters were tested in a multifactorial analysis using the Cox's forward stepping proportional hazard model. Five parameters were significantly associated with a lower survival function: presence of necrosis in the tumor (P = .001), squamous pattern (P = .002), age over 45 years (P = .004), presence of oxyphil cells in the tumor and absence of cells with intermediate cytoplasm (P = .025), less than 50% of calcitonin immunoreactive cells in the tumor (P = .04).
Mediastinal B-cell lymphoma (MBL) is a distinct variant of aggressive non-Hodgkin's lymphoma with characteristic clinical and biological features but less well-defined histomorphology. We reevaluated 124 biopsy specimens from 109 MBL patients of an Italian/French/German retrospective clinical study. MBL was primarily diagnosed on clinical and histological grounds in conjunction with the detection of CD20 expression by immunohistology. Cytologically, MBL features limited intralesional but considerable interindividual cytological diversity, ranging from medium-sized to very large, atypical cells. Sclerosis and necrosis are restricted to extrathymic and extranodal sites of involvement, predominantly the lung, as is angioinvasion, which predominantly affects larger vessels. The medium-sized and the large cell variants resemble marginal zone lymphoma variants, whereas the very large cell variant of MBL has not so far been found to have any extramediastinal counterpart. We conclude that MBL displays a broad morphological spectrum covering more than is implied by the term "diffuse large cell lymphoma." Because statistical analysis of cytological and histological criteria failed to correlate with prognosis in this comprehensive group of patients, we think it inadvisable further to subclassify MBL.
We have investigated microRNA (miRNA) expression profiles of gastric cancer and the clinicopathologic significance of miR-10b expression in gastric carcinoma. miRCURY LNA Arrays (v.16.0; Exiqon, Vedbaek, Denmark) were used to screen miRNAs in 17 gastric cancers. Reverse transcriptase polymerase chain reaction was performed to determine the expression of miR-10b in 56 gastric tumors. Expression of miR-10b in 436 paraffin-embedded cancer tissues was also investigated. In gastric cancer, 49 miRNAs were overexpressed by 2.0-fold or greater, and 39 miRNAs were down-regulated by 1.5-fold or greater, whereas miR-10b was up-regulated by 2.98-fold. miR-10b was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage, and prognosis. In stages I, II, and III, the 5-year survival rate of patients with high levels of miR-10b expression was significantly lower than that in patients with low levels of expression. In stage IV, the expression level of miR-10b did not correlate with the 5-year survival rate. miR-10b may play an important role in progression and prognosis of gastric cancer.
Five cases of fatal neonatal echovirus type 11 infection were observed in the Boston area during the summer and fall of 1979. Four of the mothers experienced gastroenteritis with fever and abdominal cramps late in the third trimester of pregnancy. The clinical course of each case was characterized by jaundice, hepatosplenomegaly, and progressive hepatic failure; all five infants were severely hypotonic. At autopsy massive hepatic and adrenal hemorrhage and necrosis, with evidence of consumption coagulopathy, were found. Echovirus type 11 was isolated from various sites before and after death. The histopathologic features and epidemiologic aspects of these cases are briefly discussed.
Primary synovial sarcoma (SS) of the lung is rare and may create diagnostic challenges. We reviewed 11 cases of pulmonary SS (PSS) confirmed by the presence of a tumor-specific SYT-SSX fusion gene to verify their clinicopathologic features including immunohistochemical and genetical profiles. The tumors occurred in 4 men and 7 women (age 29 to 81 years; mean age, 58; median age, 50), and ranged in size from 2 to 15.5 cm (mean, 9 cm). Of the 11 tumors, 10 were a monophasic fibrous type and 1 was a poorly differentiated type. Mitotic rate ranged from 8 to 43 per 10 high-power fields. All cases showed at least focal immunohistochemical positivity for AE1/AE3, CAM5.2 and/or epithelial membrane antigen. High proliferating cell nuclear antigen labeling index (>20%) was found in 8 of 10 cases (80%). Eight (90%) of 9 cases were negative for E-cadherin, and 1 case (10%) exhibited reduced expression of the molecule. The aberrant expression of beta-catenin within cytoplasm and/or nuclei was observed in 6 of 9 (67%) cases. SYT-SSX1 and SYT-SSX2 fusion gene transcripts were detected in 9 and 2 cases, respectively. In 10 patients with follow-up, 3 (30%) had local recurrences, and 4 (40%) developed distant metastases. Five (50%) patients died of the tumor 1 to 9 years after surgery, and 5 (50%) were alive and disease-free in the period ranging from 3 months to 5.5 years. In conclusion, PSS tends to occur in older patients and shows an aggressive behavior probably due to its anatomical location and large tumor often resulting in incomplete resection and high proliferative activity.
Eleven primary spindle cell carcinomas (SpCCs) of the gallbladder are reported. They occurred in eight women and three men ranging in age from 59 to 80 years (mean age, 66.5 years). Histologically, the tumors showed interlacing bundles of atypical spindle cells with eosinophilic cytoplasm, oval to elongated nuclei, and conspicuous nucleoli. Eight SpCCs contained tiny foci of neoplastic glands similar to those seen in adenocarcinoma, and two of these cases also had small foci of neoplastic squamous epithelium. A gradual transition between the squamous cell carcinoma and the spindle cell component was observed in one tumor. Immunohistochemically, all SpCCs were positive for at least one of the epithelial markers (epithelial membrane antigen, nine cases; AE1/AE3, nine cases; carcinoembryonic antigen, three cases; and EAB 903, one case), and the tumor cells also were immunoreactive to mesenchymal marker (vimentin, eight cases), muscle markers (alpha-smooth muscle actin, one case; desmin, one case), and histiocytic marker (HAM 56, one case). Abnormalities in tumor suppressor gene p53 expression also were found in two of the 11 SpCC cases using monoclonal antibody PAb 1801. In six cases for which data were available flow cytometry revealed aneuploidy in three SpCCs (50%). The survival curve of the SpCC cases (mean survival, 9 months) was less favorable than that of 224 cases of adenocarcinoma of the gallbladder (mean survival, 81 months) (P = .0011). These results indicate that SpCC of the gallbladder is an epithelial tumor with sarcomatoid components and its prognosis is unfavorable.
A series of 19 paraffin-embedded sinonasal papillomas (four squamous papillomas, three fungiform papillomas, nine inverted papillomas, and three cylindrical cell papillomas) were investigated for evidence of human papillomavirus (HPV) infection using immunohistochemistry (polyclonal antibody to HPV capsid antigen), in situ hybridization (DNA probes for HPV 6/11, 16/18, and 31/33/35), and the polymerase chain reaction (primers and probes for HPV 6, 11, 16, 18, and 33). All three fungiform papillomas were positive by all three techniques: immunohistochemistry, in situ hybridization for HPV 6/11, and the polymerase chain reaction for HPV 11. None of the other lesions contained detectable HPV using the specific probes included in this study. These results support the continued classification of fungiform papilloma as a distinctive variant of schneiderian papilloma characterized by a predominantly exophytic growth pattern and an association with HPV 11.
Matrix metalloproteinase 11 (stromelysin-3) has recently been reported to play a key role in human tumor progression and poor clinical outcome. The aim of this study was to investigate the significance of matrix metalloproteinase 11 expression in gastric cancer. Using real-time quantitative reverse-transcription polymerase chain reaction analysis and immunohistochemistry, we studied matrix metalloproteinase 11 expression levels in non-malignant gastric tissues and in gastric cancer tissues. The association between matrix metalloproteinase 11 expression levels and tumor stage and grade, as well as metastatic potential, was analyzed. Our results show that matrix metalloproteinase 11 expression was significantly higher in gastric cancer specimens compared with nonmalignant tissues at both transcriptional and protein levels, indicating its positive role in the development of gastric cancer. In addition, increased matrix metalloproteinase 11 expression levels were associated with advanced-stage and high-grade tumors, suggesting its involvement in the progression of gastric cancer. More importantly, increased matrix metalloproteinase 11 expression in gastric cancer specimens was correlated with increased expression of IGF-1, a molecule known to stimulate the proliferation, enhanced survival, and migration of cancer cells. Our results demonstrate that matrix metalloproteinase 11 is a novel factor in the development and progression of gastric cancer and suggest that matrix metalloproteinase 11 is a marker for advanced gastric cancer.
Chromosome 11 abnormalities were detected by fluorescence in situ hybridization (FISH) technique and compared with DNA ploidy in 24 surgically removed pituitary adenomas. The tumors were diagnosed and classified by histology, electron microscopy, and pituitary hormone immunocytochemistry. They included 2 densely granulated somatotroph (DG-SM) and 4 sparsely granulated somatotroph (SG-SM) adenomas, 3 SG lactotroph (LT), 2 mixed somatotroph-lactotroph (SM-LT), 4 functioning corticotroph (CRT), 1 silent CRT subtype 1, 1 thyrotroph, 1 mixed thyrotroph-somatotroph, 2 gonadotrophs, and 4 null cell adenomas. FISH analysis with an alpha-satellite DNA probe specific for chromosome 11 showed numerical abnormalities in 16 functioning (94%) and 5 nonfunctioning (71%) adenomas. Ten functioning tumors showed aneuploid histograms, whereas the remaining and all nonfunctioning adenomas were diploid. Aberrant chromosome 11 signals were noted mostly in aneuploid adenomas involving 17% to 100% of their cell population. The severity of chromosome 11 aberrations in adenomas containing extra copies often correlated with a higher DNA index (DI). Monosomy 11 as dominant aberration was noted in a mixed SM-LT and to a lesser degree in 3 CRT adenomas involving 21% to 97% of their cell population. Two of these CRT adenomas were associated with normal DI, whereas the remaining third showed a high DI, indicating increased copy number of chromosomes other than of chromosome 11. In conclusion, chromosome 11 abnormalities are common in all types of pituitary adenomas, occurring more frequently in functioning tumors. Specific numerical abnormalities, such as monosomy and trisomy, tend to be associated with certain adenoma types, whereas tumors with extra chromosome 11 copies often exhibit aneuploid histograms.
The aims of this investigation were to compare quantitative with qualitative analysis of fluorescent in situ hybridization (FISH) centromere signals in interphase breast cancer cell nuclei and to evaluate the possible clinical utility of detecting numerical abnormalities of chromosomes 11 and 17 by FISH in the preoperative prediction of breast cancer histological grade. Commercial digoxigenin-labeled centromere probes to chromosomes 11 and 17 were hybridized to 69 malignant aspirates with histological follow-up. Aspirates were categorized as disomic or aneusomic for chromosomes 11 and 17 qualitatively; a subset of aspirates was also analyzed quantitatively. The quantitative and qualitative approaches resulted in almost identical categorisation. There was a significant association between the qualitative categorization of aspirates as aneusomic or disomic, the histological grade of the excised tumours (P = .0695, n = 69), and the cytological grade of the clinical aspirates (P = .006, n = 35). Although histological grade III tumors were almost invariably polysomic for one or both chromosomes, polysomy was also detected in grade I and II tumors. Qualitative FISH analysis was shown to be more sensitive than cytological grading in predicting histological grade III but was of lower specificity and was therefore not clinically useful.
Juxtaglomerular cell tumor (JGCT), first described in 1967, is a rare tumor of the kidney that derived from specialized smooth muscle cells of the wall of the glomerular afferent arteriole. Less than 100 cases have been published, mainly as isolated case reports or small series. JGCTs are considered benign, but the clinical follow-up is short in most reported cases. Only 1 metastatic case has been reported to date, raising the question of tumors of uncertain malignant potential rather than clearly benign neoplasms. Genomic features have been studied in only 2 cases that showed gain of chromosome 10 as well as loss of chromosomes 9, 11q, and X. The present work studied the genomic characteristics of 2 additional cases of JGCT by comparative genomic hybridization. Similarly to the 2 previously reported cases, these 2 tumors showed loss of chromosomes 9 and 11, suggesting recurrent chromosomal imbalances. In addition, 1 case showed gain and loss of entire chromosomes, similar to a previous case studied by karyotyping. Such an aneuploid karyotype may reflect a potential for malignancy as previously reported. Thus, JGCT might be better considered as a tumor of uncertain malignant potential and then necessitates a prolonged follow-up. Future clinicopathologic and genomic studies of large retrospective and prospective series may help to better understand the biology of this fascinating entity.
Rosai-Dorfman disease (RDD), originally described as sinus histiocytosis with massive lymphadenopathy, is a rare histiocytic proliferative disorder with a distinctive microscopic appearance. Formerly thought to be a process limited to lymph nodes, involvement by RDD has now been documented in many organ systems, notably bone, skin and soft tissue, central nervous system, eye and orbit, and upper respiratory tract. The digestive system, however, is affected only exceptionally, as reflected by the existence of only a handful of individual case reports. In this article, we report 11 patients in which the disease involved intestinal tract, liver, or pancreas, and describe the most salient clinicopathologic features. The specific site of involvement within the digestive system was gastrointestinal tract in 5, liver in 5, and pancreas in 1. Most patients also had evidence of disease in other extranodal sites, as well as in 1 or more lymph node groups.
Human papillomavirus (HPV) types 6 and/or 11 have been associated with benign lesions, while types 16, 18, 31, and 33 are prevalent in malignant lesions. This case report describes the findings in a verrucous carcinoma of the leg, which was examined for HPV types 11, 16, and 18 by in situ DNA hybridization. The lesion gave positive results for HPV subtypes 11 and 18, a combination that, to our knowledge, has not been previously reported in this neoplasm.
We describe the histopathologic changes of skin, muscle, vessels, and fascia in 11 patients with eosinophilia myalgia syndrome, a newly described entity that has been linked to the ingestion of L-tryptophan. This syndrome is defined clinically by severe incapacitating myalgias and a peripheral eosinophilia. Arthralgias, edema of the extremities, morbilliform rashes, skin induration, weakness, fatigue, and respiratory weakness may be present as well. The earliest apparent histologic changes were observed at the septa between subcutaneous fat lobules and in the deep dermis or fascia. The septa and fascia were infiltrated with a sparse mixture of lymphocytes and histiocytes. In the deep fascia, in addition to inflammatory cells, there were distinctive, reactive mesenchymal cells that showed features of both histiocytes and fibrocytes. Minimal tissue eosinophilia was seen despite the extent of blood eosinophilia. Dermal thickening and homogenization of collagen bundles occurred with replacement of fat and adnexa (changes indistinguishable from scleroderma or morphea). Vessel walls in the dermis and fascia showed thickening and endothelial swelling, but no overt vasculitis was noted. Skeletal muscle biopsies showed a perimysial, epimysial, and/or fascial inflammatory infiltrate of lymphocytes and distinctive reactive mesenchymal cells with some eosinophils. Minimal myofiber atrophy, regeneration, or necrosis was seen despite the clinical history of severe myalgias in almost all patients. This syndrome should help gain insight into the mechanisms of fibrosis in environmental-induced, scleroderma-like syndromes and in idiopathic, scleroderma-like disorders as well.
Colonic carcinomas with minimal or no glandular differentiation are a heterogeneous group of neoplasms which differ in their histologic appearance, clinical features, prognosis and molecular characteristics. Since 1990, we prospectively identified 11 patients with a predominantly solid (nonglandular) adenocarcinoma of the colon for which the term medullary adenocarcinoma of the colon (MAC) is proposed. The clinical, histological, histochemical, and immunohistochemical features of these neoplasms were studied. All patients with MAC were women with tumors in the cecum or proximal colon. Histological analysis showed nests or trabeculae of regular small to medium-sized cells with moderate amounts of eosinophilic cytoplasm; some cells contained mucin vacuoles. The nuclei had an open chromatin pattern and exhibited prominent nucleoli. Lymphatic permeation was present in most cases. Immunohistochemical reactions were positive for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen. Despite its histological resemblance with endocrine tumors, MAC is negative for endocrine markers. Of the eight patients for whom follow-up is available, four patients (two Dukes B and two Dukes C) are alive and well 1 to 4 years after surgery, one patient (Dukes C) died of tumor, one patient is alive with liver metastasis 4 years after surgery, and two patients died in the postoperative period. MAC appears to be a distinctive clinicopathologic entity. This tumor should be distinguished from other more aggressive, nonglandular tumors of the colon.
Juvenile hemangiomas are common, benign vascular tumors of infancy. These lesions enlarge rapidly through cellular hyperplasia during the first year of life and then involute over several years. Distinctive histopathologic features of hemangiomas diminish during this evolution, and differentiation from vascular malformations becomes increasingly difficult. This distinction has important therapeutic implications, as juvenile hemangiomas differ from malformations in natural history and in potential for recurrence. We report here that high endothelial immunoreactivity for the erythrocyte-type glucose transporter protein GLUT1 is a specific feature of juvenile hemangiomas during all phases of these lesions. In a retrospective study, we found intense endothelial GLUT1 immunoreactivity, involving more than 50% of lesional microvessels, in 97% (139 of 143) of juvenile hemangiomas from patients aged 1 month to 11 years. No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens. Abundant Ki-67 positivity in these latter lesions established that GLUT1 expression does not simply reflect mitotically active endothelium. Focal GLUT1 immunoreactivity was found in 3 of 12 angiosarcomas, but not in any of 5 hemangioendotheliomas (epithelioid or infantile kaposiform). These findings establish GLUT1 immunoreactivity as a highly selective and diagnostically useful marker for juvenile hemangiomas. Because high levels of endothelial GLUT1 expression in normal tissue are restricted to microvessels with blood-tissue barrier function, these findings also have implications for the molecular and developmental pathogenic mechanisms of juvenile hemangiomas.
This article describes 11 cases of myxoid chondrosarcoma (MCS), with 10 arising in soft tissues and one developing in bone. Most of the tumors (six) were located in the lower extremities. Two lesions developed in the fingers, a previously unreported location for MCS. Four cases showed secondary bone destruction, which is a rare feature of this tumor. S100 protein was expressed by tumor cells in all the specimens. Four out of eight tumors studied by electron microscopy contained intracisternal microtubular structures. Two tumors showed areas of spindle cell proliferation that merged with the areas of typical myxoid pattern. The cells in these areas had fibroblastic/myofibroblastic features by electron microscopy and were found to express cytokeratin by immunohistochemistry. The concomitant expression of cytokeratin and S100 protein in the spindle cells suggests that they represent a less differentiated cartilaginous component with unusual features. The clinical significance of the presence of such spindle cell areas presently remains unknown. Although myxoid chondrosarcoma is a slow-growing tumor, it has a high potential for metastases. Four of 11 patients in this series developed metastases.
Eleven cases of an unusual endometrial glandular proliferation associated with early pregnancy are reported. All lesions were incidental discoveries in first-trimester gestational endometria (two elective abortions; five spontaneous abortions; three hydatidiform moles; one tubal ectopic pregnancy). Most patients (nine of 11; 82%) were older than 30 years of age; associated clinical features included oligoovulation (two), hypertension (one), and obesity (one). All lesions were small and localized, and displayed similar histological features of variable severity including glandular expansion with smooth external contours; epithelial stratification (4 to 15 layers); cribriforming (focal to extensive); mitotic activity; bland nuclear cytology; and prominent intraglandular calcifications (eight cases; 72%). Although the natural history of these distinctive pregnancy-associated endometrial lesions was unknown, nine lesions were initially classified as benign, and two were interpreted as atypical endometrial hyperplasia or focal adenocarcinoma. Follow-up for an average of 34 months (range, 18 to 56) in nine patients showed no residual endometrial lesion (seven endometrial curettages and two hysterectomies). Three patients followed by curettage have subsequently completed successful pregnancies. This unusual lesion may represent a localized, endometrial proliferation induced by pregnancy; although some endometrial lesions may display striking architectural complexity, follow-up to date suggests a benign behavior.
Clinical, cytogenetic, histopathologic, and immunohistochemical data were obtained in a series of 11 small round cell tumors (SRCT) of bone and soft tissue with the translocation t(11;22) (q24;q12). Ten cases were primary in bone, and one was of extraskeletal origin. According to conventional histopathologic criteria, 10 cases were Ewing's sarcomas (ES) and one was a peripheral neuroectodermal tumor (PNET). Besides the t(11;22), six cases had additional chromosomal aberrations, including trisomy 7 and partial trisomy for the long arm of chromosome 1, which have both been described as nonspecific secondary abnormalities often associated with tumor progression. The tumors were screened for neural differentiation with an antibody panel consisting of neuron-specific enolase, S100 protein, Leu-7, chromogranin, synaptophysin, and neurofilament. Three cases of ES were positive for S100 protein. The PNET and one case of ES were positive for neuron-specific enolase. All of the remaining immunohistochemical stains were negative. Hence, five of 11 SRCT of bone or soft tissue with the t(11;22) showed morphologic and/or immunohistochemical evidence of neural differentiation. In this limited series of cases, no cytogenetic or prognostic differences could be demonstrated between cases with and without a neural phenotype. Our results support the hypothesis that SRCT of bone of soft tissue with the t(11;22) form a single biologic entity displaying varying degrees of neuroectodermal differentiation. The clinical significance of additional cytogenetic abnormalities and of morphologic or immunohistochemical evidence of neural differentiation in this group of tumors needs to be further studied.
Twenty-three conjunctival papillomas and 28 conjunctival dysplasias were examined for human papillomavirus (HPV)-DNA sequences by in situ hybridization with nick-translated 35S-labeled HPV probes. Adjacent paraffin sections were hybridized with HPV type 2, 6, 16, and 18 probes at Tm - 17 degrees C. Fifteen tissues, all papillomas, displayed positive hybridization with the HPV-6 probe. Infection with HPV-6 (or the closely related HPV-11) appeared to be responsible for most of the conjunctival papillomas of children and young adults. The presence of genital tract HPV-6 in these lesions suggests that some of the infections were acquired during passage through an infected birth canal. The lack of hybridization in adult conjunctival dysplasias indicates either that HPVs are not associated with this condition or that the probes and the technique utilized were not adequate for demonstration of this association.
Sudden infant death syndrome (SIDS) is the unexpected death of a child younger than 1 year that remains unexplained after thorough evaluation. The possibility of an underlying primary arrhythmogenic disorder has been proposed as a potential cause of SIDS. This study sought to review SIDS deaths and to perform genetic analysis in key genes that may contribute to sudden death. From 2000 to 2010, all postmortem records from the Department of Forensic Medicine in Sydney, Australia, were reviewed. Cases that gave the cause of death as "SIDS" or "undetermined" but consistent with SIDS were included. In a subset of cases, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel family of genes (HCN2 and HCN4) was analyzed. A total of 226 SIDS cases were identified; 61% were male, 41% occurred while bed sharing, and there was a peak in deaths between 2 and 4 months old. The incidence did not decrease over the study period. In a subgroup of SIDS cases (n = 46), genetic analysis identified 2 likely pathogenic variants (2/46; 4%). A novel nonsynonymous variant, HCN4-Ala195Val, predicted to be pathogenic, was identified in a female infant who died at age 4 months. A female infant aged 5 weeks carried a rare nonsynonymous variant, HCN4-Val759Ile, which is similar to previously described variants associated with cardiac arrhythmias. In conclusion, the incidence of SIDS remains constant, with no apparent decline in the last decade. The underlying cause of SIDS remains largely unknown. Mutations in cardiac ion channel genes including rare nonsynonymous HCN gene variants may play a role in the pathogenesis of some SIDS cases.
Squamous cell carcinoma evolving from squamous papilloma in both the upper and lower respiratory tract in the same patient is uncommon. The molecular mechanisms underlying the progression have not been well investigated. We herein describe a case of squamous cell carcinoma arising from respiratory papilloma in two independent occasions. The patient initially had oropharyngeal squamous cell carcinoma arising in a squamous papilloma at the age of 25 years. He subsequently developed squamous cell carcinoma in the left lower lobe of the lung, which was also associated with squamous papilloma, 8 years after the complete excision of the oropharyngeal lesion. Polymerase chain reaction-based broad-spectrum human papillomavirus DNA amplification and typing showed the presence of human papillomavirus type 11 DNA in both oropharyngeal and pulmonary tumors. Immunohistochemical studies showed that the expression status of p53, Rb, and p16 proteins was unaltered during tumor progression. These observations indicate that human papillomavirus 11-associated neoplastic transformation and tumor progression in the respiratory tract may not involve aberrant regulation of the p53 and Rb signaling pathways.